The fusion of sperm and egg lead to the combination of the father's and mother's genetic information to create a new individual. In humans, as in all mammals, sperm must reach the egg, penetrate its protective coat, fuse with the oocyte membrane, and deliver its genetic material. We have identified ion channels that are in spermatozoa, but not other tissues. CatSpers1-4 (Cation channel of Sperm) are 4 distinct genes present in all mammals, including humans, that encode 6 transmembrane-spanning ion channel protein subunits. These proteins form a sperm-specific, alkaline-activated, calcium-selective ion channel localized exclusively to the principal piece of the sperm tail. Male mice homozygous for null-mutations of any of the 4 CatSper genes are infertile but otherwise are completely normal. CatSper null sperm are unable to acquire hyperactivated motility and have reduced sperm endurance. Female mice lacking these genes appear completely normal, and have normal fertility. The CatSper protein spans the plasma membrane of the spermatozoan tail, and thus its extracellular surface is accessible to small molecules. The purpose of this proposal is to develop high throughput, and secondary verification screens, to identify drugs that block CatSper activity. A CatSper blocker should readily access binding sites on the external surface of sperm and thus prevent fertilization. Since CatSper is only expressed in mature sperm, a specific blocker should have no side effects on other cells and tissues, testicular function, or sperm development. PUBLIC RELEVANCE: We aim to develop an effective and safe male contraceptive. The drug will be targeted against a unique protein on the surface of mature sperm cells, called CatSper. CatSper is required for male fertility. Since the protein is only present on mature sperm, a drug inhibiting this molecule should have no effect on normal testicular or sperm development, and no effect on other organs within males or females.